Obesity is a pandemic disorder that is characterized by accumulation of adipose tissue and chronic-low grade inflammation driven primarily by adipose tissue macrophages (ATMs). Macrophages include a heterogeneous population of cells found in most tissues of the body. These cells are innate immune cells that are capable of performing a broad spectrum of functions. Macrophages display a remarkable plasticity between phenotypes classified along a continuum between the extremes of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages.
It is known that ATM polarization from pro-(M1) to anti-(M2) inflammatory phenotype influences insulin sensitivity and energy expenditure, though the specific mechanisms involved are unclear. M1 macrophages are known to produce pro-inflammatory cytokines (such as IL-12, TNFα, and IL-1β), reactive oxygen species and nitric oxide, and proteases (such as MMP 2 and 9).
During obesity, M1 ATMs dominate the adipose tissue in both phenotype and abundance, promoting insulin resistance and chronic low-grade inflammation. Due to vast disparities seen in ATM functionality between lean and obese individuals, ATMs have been suggested to play a substantial role in determining development of obesity-related pathologies. Therapeutic strategies that decrease ATM-dependent inflammation have been heavily investigated due to the tight correlation of macrophage-dependent inflammation and insulin resistance.
Notch signaling is highly conserved juxtacrine signaling utilized by numerous cell types including macrophages and adipocytes and plays key roles in metabolic and inflammatory processes. Binding of Notch receptors (Notch1-4) by Delta-like and Jagged ligands (DLL1, -3, -4 and JAG1, -2) initiates proteolytic release of the Notch intracellular domain (NICD) allowing it to translocate to the nucleus and activate Jκ-Recombination Signal-Binding Protein (RBP-J)-dependent transcription.
In macrophages, Notch1 signaling promotes pro-inflammatory polarization through IRF8 and NF-κB transcriptional pathways, while in adipocytes, Notch1 signaling inhibits white adipose tissue browning and energy expenditure, and promotes insulin resistance. Additionally, blockade of the canonical Notch1 ligand DLL4 improves atherosclerosis and metabolic disease, indicating DLL4-Notch1 signaling is directly involved in the crosstalk of inflammatory and metabolic pathways.
MicroRNAs and DNA methylation have been associated with development of aging-associated pathologies including obesity, atherosclerosis, and cancer. MicroRNAs (miRNA, miR) are short (˜22 nucleotide long) non-coding RNAs that post-transcriptionally inhibit protein translation by binding the 3′ untranslated region (3′UTR) of target mRNAs. Because approximately 60% of protein-coding genes are known conserved targets of miRNAs, they have emerged as important regulators of biological functions such as immune system development and inflammatory responses. DNA methylation occurs when methyl groups are added to cytosines by DNA methyltransferases (DNMT). These methylated cytosines primarily reside in CpG islands near transcription start sites and repress gene transcription by blocking binding sites for transcription factors through chromatin condensation.
What are needed in the art are therapeutics for treatment of obesity related pathologies such as obesity related inflammation and insulin resistance. In particular, therapeutics including miRNAs that can be utilized in treatment of obesity-related pathologies through inhibition of polarization of ATMs to inflammatory phenotypes and/or modification of expression of inflammatory-related cytokines would be of great benefit.